11-60064278-C-A

Position:

chr11-60064278-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006138.5(MS4A3):c.311C>A(p.Thr104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,604,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MS4A3
NM_006138.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.504

Variant links:

Genes affected

MS4A3 (HGNC:7317): (membrane spanning 4-domains A3) This gene encodes a member of the membrane-spanning 4A gene family. Members of this protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This family member likely plays a role in signal transduction and may function as a subunit associated with receptor complexes. The gene encoding this protein is localized to 11q12, among a cluster of related family members. Alternative splicing may result in multiple transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

MS4A3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05268562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MS4A3	NM_006138.5 linkuse as main transcript	c.311C>A	p.Thr104Asn	missense_variant	4/7	ENST00000278865.8
MS4A3	NM_001031809.2 linkuse as main transcript	c.173C>A	p.Thr58Asn	missense_variant	3/6
MS4A3	XM_011545363.4 linkuse as main transcript	c.131C>A	p.Thr44Asn	missense_variant	3/6
MS4A3	NM_001031666.2 linkuse as main transcript	c.-59C>A		5_prime_UTR_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MS4A3	ENST00000278865.8 linkuse as main transcript	c.311C>A	p.Thr104Asn	missense_variant	4/7	1	NM_006138.5	P1	Q96HJ5-1
MS4A3	ENST00000358152.6 linkuse as main transcript	c.173C>A	p.Thr58Asn	missense_variant	3/6	5			Q96HJ5-2
MS4A3	ENST00000395032.6 linkuse as main transcript	c.-59C>A		5_prime_UTR_variant	2/5	2			Q96HJ5-3
MS4A3	ENST00000525686.1 linkuse as main transcript	c.238C>A	p.Pro80Thr	missense_variant, NMD_transcript_variant	4/7	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000699

AC:

AN:

243280

Hom.:

AF XY:

0.0000456

AC XY:

AN XY:

131562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000501

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1452570

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722382

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000393

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000521

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.311C>A (p.T104N) alteration is located in exon 4 (coding exon 3) of the MS4A3 gene. This alteration results from a C to A substitution at nucleotide position 311, causing the threonine (T) at amino acid position 104 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.67

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.50

T;.;.

M_CAP

Benign

0.0030

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.014

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.071

T;T;T

Polyphen

0.021

B;B;B

Vest4

0.37

MutPred

0.30

.;Loss of stability (P = 0.1042);.;

MVP

0.092

MPC

0.015

ClinPred

0.075

GERP RS

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over